Journal of Bone and Mineral Research最新文献

Osteoporosis is a major health concern in older individuals. Efficient case-finding is essential for timely risk assessment and treatment for high-risk patients. To prevent fractures and reduce the risk of subsequent disability, approaches offering clinically sufficient sensitivity with acceptable specificity are warranted. Although pharmaceutical osteoporosis treatment is effective, it is often diagnosed at a late stage, for instance following a fracture. The aim of this study was to extend the existing Fracture Risk Evaluation Model (FREM), which identifies individuals at risk of an imminent (one-year) major osteoporotic fracture (MOF) based on administrative health data. This extension (FREMVer2) included data on morbidity and medications and evaluated age-specific risk cut-offs to enhance the risk assessment of MOF and hip fracture (HF) risk, respectively. We included the entire population of Denmark aged ≥45 yr at baseline (2022; N = 2 493 180), not previously diagnosed with osteoporosis or receiving osteoporosis treatment. The cohort was divided into four groups stratified by sex and age (<65 yr, ≥65 yr). Each of the four groups was randomly split into a 60% development, a 20% model validation, and a 20% cut-off validation cohort. All diagnoses from Danish hospitals and filled prescriptions from Danish pharmacies from 2007-2021 were used as possible predictors for MOF. These predictors correspond to information that in Denmark is automatically transferred to general practitioner's electronic health records; hence, prediction would be possible in general practice. Models were constructed by logistic regression with LASSO regularization, determining the preferred regularization hyper parameter by cross-validation and forcing categorical age to be included. Across subgroups models obtained poor to acceptable AUCs of 0.656 to 0.714 for MOF, and acceptableAUCs of 0.728 to 0.764 for hip fractures, and achieved sensitivities of around than 80% or higher in almost all subgroups. This performance, together with the available predictors, makes FREMver2 a feasible decision support system as a step towards an opportunistic screening program in health care settings with access to administrative data.

Current fracture risk assessment does not directly include fall probability, despite most hip fractures resulting from falls. Additionally, the role of trochanteric soft tissue thickness (TST) in hip fracture risk remains unclear. This study aimed to develop a subject-specific fall risk tool and test whether incorporating fall probability and TST improves hip fracture prediction beyond FRAX alone in older adults from the AGES-Reykjavik study. Baseline data from 3242 individuals (58% women) were used to predict repeated falls (≥2 in 12 months) at follow-up (~5 years later) via multivariate logistic regression, considering age, sex, fall history, neuromuscular function, dynamic balance, and medication use. In a case-cohort study (698 hip fractures, 1348 controls; median follow-up 10 years), Cox proportional hazards models assessed hip fracture risk. We compared the predictive value of fall probability and TST combined with FRAX against FRAX alone using time-dependent AUC at 5-, 10-, and 16-year follow-up. At follow-up, 295 individuals had ≥2 falls in the past year. The best model for future falls included a timed up-and-go test, fall history, and grip strength. The probability of falling predicted incident hip fracture and improved hip fracture prediction beyond FRAX, in both men and women. The improved predictive value of fall risk was greater among men than women (e.g. AUC for predicting 10 yrs hip fracture risk, 0.83 (95%CI 0.79-0.87) in men vs 0.75 (95%CI 0.72-0.78) in women). Lower TST was linked to higher hip fracture risk in women but not men. However, adding TST to a model with fall probability and FRAX among women did not enhance time-dependent AUC (p>0.10). In conclusion, fall probability significantly improves hip fracture prediction beyond FRAX, particularly in men. Thus, subject-specific fall risk assessment may enhance clinical evaluation of hip fracture risk in older adults.

Background: Early-onset osteoporosis (EOOP) is a rare form of primary osteoporosis defined by major skeletal fractures or low bone mineral density (BMD) that occurs in early age. However, the characteristics of the extracellular matrix that may contribute to bone fragility are unknown.

Purpose: We explored the microarchitecture and bone matrix composition in transiliac bone biopsies (BBs) obtained from adults with EOOP.

Methods: We compared EOOP BBs to historical control BBs. Microarchitecture was measured by μ-CT and bone matrix composition by Raman microspectroscopy and FTIR spectroscopy. Mechanical response of the bone matrix was investigated by nanoindentation. The contribution of each parameter was assessed by principal component analysis (PCA).

Results: We compared 18 BBs for EOOP patients (mean [SD] age 34 [8] years, lumbar-spine BMD Z-score -2.05 [1.04]) to 19 BBs for age-matched healthy individuals. Patients had vertebral fractures only (n=7), peripheral fracture only (n=6) and both vertebral and peripheral fractures (n=3). EOOP and controls had similar bone volume (bone volume/total volume, p=0.741). As compared with controls, EOOP BBs showed lower trabecular separation (p=0.026) and higher trabecular connectivity density (p<0.001); cortical thickness was lower in EOOP BBs (p<0.01). Also, GAG/Amide III and hydroxyproline/proline ratios as well as accumulation of AGEs were greater in EOOP than controls (all p<0.0001). Moreover, tissue mineralization was lower in EOOP than controls, as shown by v1PO4/CH2 ratio, mineral maturity crystallinity and crystal size index (all p<0.005). Hardness, indentation modulus and maximum load were all altered in EOOP. PCA revealed greater contribution of both the organic and mineral matrix phase at the trabecular and cortical EOOP bone rather than bone microarchitecture.

Conclusion: The matrix composition of bone showed greater damage of the organic matrix phase and reduced mineralization in EOOP patients than controls, which may explain the high risk of fracture in EOOP patients and may differentiate EOOP from other bone diseases.

The Fracture Risk Assessment Tool (FRAX) is widely used in osteoporosis management, yet its performance across diverse racial, ethnic, and genetic populations remains uncertain. We evaluated the accuracy of FRAX in predicting fracture risk, with and without bone mineral density (BMD) measurements, among 27,512 postmenopausal women aged 50 to 79 years participating in the Women's Health Initiative (WHI) with 10 years of follow-up. FRAX-predicted fracture risks were compared to observed outcomes, stratified by race/ethnicity and genetic risk categories derived from a Genome-Wide Polygenic Score (GPS), calculated using 103,155 genetic variants via the LDpred algorithm and UK Biobank GWAS data. FRAX with BMD information substantially overestimated fracture risk for African American women by 82% (hazard ratio [HR], 0.18; 95% CI, 0.10-0.36) and Hispanic women by 48% (HR, 0.52; 95% CI, 0.31-0.87), compared with non-Hispanic White women (both P < .001). Conversely, FRAX with BMD information significantly underestimated fracture risk in women with the highest genetic risk (top 5%; HR, 2.15; 95% CI, 1.22-3.68; P < .001), compared with the low GPS reference group. Calibration analyses revealed systematic inaccuracies, highlighting racial disparities in overestimating fracture risk and genetic disparities in underestimating fracture risk predictions. Sensitivity analyses confirmed these findings persisted regardless of estrogen use. Our results underscore critical limitations of FRAX, suggesting that integrating genetic risk profiling and implementing race-specific recalibrations can substantially improve fracture risk prediction accuracy, promote equity in osteoporosis care, and support personalized clinical decision-making.

The gut microbiome is associated with bone mass acquisition, yet evidence in childhood remains limited. Given that lower peak bone mass predicts osteoporosis in later life, understanding early influences is important. This analysis explores the association between the early life gut microbiome and bone health in later childhood. Data were obtained from 700 children recruited in pregnancy and followed prospectively within the Copenhagen Prospective Studies on Asthma in Childhood2010 cohort, a population-based mother-child cohort. The infant gut microbiome was measured at 1 wk (n = 445), 1 mo (n = 492), 1 yr (n = 508), 4 yr (n = 350), and 6 yr (n = 327) of age by 16S ribosomal ribonucleic acid amplicon sequencing targeting the fourth variable region. Total body less head BMD and area-adjusted BMC were measured by DXA at 6 yr of age. Associations were investigated by multiple linear regression, permutational analysis of variance, differential abundance analysis, and Random Forest machine learning. There were few associations between the early-life gut microbiome and bone health outcomes at age 6. We found negative associations between alpha (within-sample) diversity and area-adjusted BMC at 4 yr. Beta (between-sample) diversity of the gut microbiome at 6 yr was associated with concurrent BMD. Escherichia-Shigella abundance at 1 mo of age was associated with lower BMD. Sutterella abundance at 1 yr was associated with lower BMD and area-adjusted BMC at 6 yr. There were no other associations between the gut microbiome and bone outcome measures at any time point. In a well-powered unselected cohort study with longitudinal sampling of the gut microbiome, there were some suggestive but no consistent associations between the early gut microbiome and bone health outcomes at 6 yr of age.

We aimed to investigate associations between diabetes mellitus and incident fracture, stratified by diabetes type (1 or 2), disease duration and microvascular complications of diabetes. This prospective cohort analysis used data from the UK Biobank, a large population-based cohort of participants recruited 2006-2010 at age 40-69 yr. The exposure was type 1 or type 2 diabetes at baseline, with the outcome of first incident osteoporotic fracture. Poisson regression was used to calculate incidence rate ratios (IRRs) for osteoporotic fracture to investigate prospective relationships between diabetes type 1 or 2 and fracture risk independent of traditional clinical risk factors, estimated BMD by heel ultrasound (eBMD), adiposity, and C-reactive protein (CRP). The role of diabetic microvascular complications and associations between diabetes duration and fracture risk were studied. There were 498 949 participants (271 882 women, mean age 56 yr; 227 067 men, 57 yr). In fully adjusted models, type 1 and 2 diabetes were associated with increased fracture risk [type 1; IRR: 2.93 (95% CI: 2.37, 3.62); type 2: 1.25 (1.14, 1.38)], similar by sex. The magnitude of risk associated with type 2 diabetes increased with the duration of disease. Increasing number of microvascular complications was associated with greater fracture risk [any vs no complications, IRR 2.03 (1.57, 2.62)]. Diabetes is associated with increased risk of fracture (magnitude of effect greater in type 1 than type 2 diabetes). Associations were partly independent of traditional risk factors, adiposity, eBMD, and CRP. Type 2 diabetes disease duration and the presence of microvascular complications in both types were dose-dependent risk factors for fracture.

Bone remodeling is a dynamic process regulated by the activities of osteoclasts and osteoblasts. Imbalances in this process can lead to osteoporosis, a condition characterized by low bone mass and increased fracture risk. The homeodomain protein TG-interacting factor 1 (Tgif1) has been previously identified as a key regulator of osteoblast function. Here, we investigate the cell-autonomous role of Tgif1 in osteoclasts. Our findings reveal that Tgif1 is expressed in osteoclast precursors, with its expression increasing during RANKL and M-CSF-induced differentiation. Deletion of Tgif1 in the osteoclast lineage impairs osteoclast differentiation and resorption capacity, reducing aging-related bone loss in mice in vivo. Mechanistically, Tgif1 restricts ERK1/2 dephosphorylation by suppressing protein phosphatase 2A (PP2A), an ERK1/2 phosphatase. Inhibition of PP2A restores impaired differentiation of Tgif1-deficient osteoclasts, confirming its involvement in this process. These findings establish Tgif1 as an important regulator of osteoclast differentiation, function, and bone resorption, offering new insights into molecular mechanisms controlling bone mass maintenance.

Emerging anti-osteoporosis therapies might present varied mechanisms of action and demand active control groups or sequential therapies due to ethical or mechanistic reasons. We previously showed a strong association between treatment-induced changes in total hip BMD (THBMD) at 12 and 24 mo and reduced fracture risk in placebo-controlled trials. We determined the surrogate threshold effect: the minimum THBMD difference (active-placebo) in a trial that would predict a significant reduction in fracture risk in trials. In this analysis, we investigated whether these associations are influenced by drug mechanism of action or trial design, including treatment with an anabolic followed by an antiresorptive compared to active control or placebo. We analyzed individual patient data from 22 randomized, placebo-controlled trials (17 antiresorptive, 3 PTH analogs, 1 odanacatib, and 1 romosozumab placebo-controlled phase), and 3 trials of an anabolic followed by an antiresorptive (1 PTH analog and 2 romosozumab). We established treatment-related differences in THBMD changes, calculated fracture risk reductions for radiologic vertebral and all clinical fractures, and estimated study-level associations between these features via meta-regression. We found consistent associations between treatment-related THBMD changes and fracture risk reduction across different drug mechanisms and trial designs. Among placebo-controlled trials, the r2 values for vertebral fractures were 0.73 (p = .0001) and 0.78 (p = .0002) at 24 mo, and 0.59 (p = .0003) and 0.70 (p = .0007) at 12 mo for all drugs vs only antiresorptive drugs, respectively. Similarly, for all clinical fractures, the r2 were 0.71 (p < .0001) and 0.65 (p = .0009) at 24 mo and 0.46 (p = .0007) and 0.51 (p = .002) at 12 mo for all drugs vs only antiresorptive drugs. For trials of an anabolic followed by an antiresorptive, the association between THBMD change and fracture risk reduction was similar to that for the placebo-controlled monotherapy trials. Our analyses indicate robust associations between treatment-induced THBMD changes and fracture risk reduction across various anti-osteoporosis therapies and trial designs, suggesting that treatment-induced changes in THBMD predict anti-fracture efficacy regardless of drug mechanism or trial design.